PROJECT SUMMARY: Synaptopathy, loss of functional synapse between hair cells and their afferent neurons, is thought to be of central importance in the development of auditory deficits such as speech perception and sound discrimination in noisy environments. Noise exposure during the lifetime is thought to be an important contributing factor to synaptopathy. Investigation of this problem is difficult in humans in part due to the difficulty confirming loss of auditory synapses in living humans and the limited knowledge of the effects of biological variables such as age on noise-induced synaptopathy. Importantly, synaptopathy can experimentally investigated in animal models such as mice, which have emerged as a leading research tool in auditory neuroscience. The overall objective of the proposed experiments is to identify age-dependent effects of noise exposure in a mouse model of noise-induced synaptopathy. The proposed studies will apply a battery of well-defined psychoacoustic tests in a well-controlled mouse model of synaptopathy. The mouse model affords us the opportunity to screen animals exposed as young or older adults to synaptopathy-inducing noise on behavioral and electrophysiological measures to detect dysfunction in addition to performing anatomical assays to confirm the pattern of auditory nerve synapse loss and central reorganization. We will pursue our objective through three aims: 1) Measure the effects of noise exposure on the perception of spectral, temporal, and intensity cues in young and old mice; 2) Measure the effects of noise exposure on the perception of spectrotemporally complex stimuli; 3) Measure central gain compensation and the underlying changes in synaptic reorganization in the auditory brainstem. We will test for synaptopathy-related perceptual deficits in young and old mice trained to detect or discriminate sounds in quiet and noise. Our preliminary data indicate that old- exposed mice cannot recover as well as younger-exposed mice, and we hypothesize that this is due to reduced central compensation in the older brain. Auditory nerve synapse numbers will be quantified in all mice so that behavioral and physiological response patterns can be correlated with patterns of peripheral synapse loss and central reorganization. The experiments outlined here will reveal a suite of behavioral measures that can be used by clinicians to reveal synaptopathy in human patients and will identify whether or not ABRs can be optimized to detect synaptopathy.